Paclitaxel, one of the most important anticancer drugs developed in the past two decades, is active against multiple types of human solid tumors (Rowinsky E K (1993) J Natl Cancer Inst Monogr 15:25–37). Paclitaxel has pleiotropic effects; for example, it enhances tubulin polymerization, promotes microtubule assembly, binds to microtubules, stabilizes microtubule dynamics, induces mitotic block at the metaphase/anaphase transition, and induces apoptosis (Parness J and Horwitz S B (1981) J Cell Biol 91:479–487; Manfredi J J et al. (1982) J Cell Biol. 94:688–696; Jordan M A, et al. (1993) Proc Natl Acad Sci USA 90:9552–9556; Jordan M A et al. (1996) Cancer Res 56:816–825; Derry W B et al. (1995) Biochemistry 34:2203–2211). The intracellular concentration of paclitaxel is critical for its pharmacological effect; drug resistance in several resistant sublines is correlated with reduced intracellular drug accumulation compared with the sensitive parent cell lines (Lopes N M et al. (1993) Cancer Chemother Pharmacol 32:235–242; Bhalla K et al. (1994) Leukemia 8: 465–475; Jekunen A P et al. (1994) Br J Cancer 69:299–306; Riou J F et al. (1994) Proc Am Assoc Cancer Res 35:160; Speicher L A et al. (1994) J Natl Cancer Inst 86:688–694).
Doxorubicin is an anticancer drug with a wide spectrum of clinical activities. It has been used clinically to treat leukemias, lymphomas, and solid tumors including breast, lung, prostate, and ovarian cancers and sarcomas (Oesterling et al. (1997) In: Cancer: Principles and Practice of Oncology (Eds, DeVita, V. T., Jr., Hellman, S., and Rosenberg, S. A., 1997); Doroshow, J. H. (1996) In: Cancer Chemotherapy and Biotherapy: Principles and Practice (Eds, Chabner, B. A. and Longo, D. L.)). Doxorubicin is one of the most effective agents against hormone-refractory prostate cancer (Smith, D. C. (1999) Urol. Clin. North Am. 26:323–331). It has been shown that in human prostate tumor histocultures, doxorubicin can induce complete inhibition of tumor cell growth with IC50 of 61 nM and complete tumor cell death with LC50 of 2.1 μM (Chen et al., (1998) Clin. Cancer Res. 4:277–282, 1998).
Drug delivery to the tumor core is necessary to prevent tumor regrowth (Erlanson M et al. (1992) Cancer Chemother Pharmacol 29:343–353; Durand R E (1990) Cancer Chemother Pharmacol 26:198–204) and is, therefore, an important determinant of treatment efficacy (Jain R K (1996) Science 271:1079–1080). Following a systemic intravenous injection, drug delivery to the tumor core involves three processes, i.e., distribution through vascular space, transport across microvascular wall, and diffusion through interstitial space in tumor tissue (Jain R K (1987) Cancer Res 47:3039–3051). When the drug is directly injected into a tumor such as by intratumoral injection or by direct instillation into peritumoral space such as in intravesical therapy of superficial bladder cancer and in the intraperitoneal dialysis of ovarian cancer, drug delivery to the tumor is primarily by diffusion through interstitial space (Nativ O et al. (1997) Int J Cancer 70:297–301; Song D et al. (1997) Cancer Chemother Pharmacol 40:285–292; Markman M (1998) Semin Oncol 25:356–360; Markman M et al. (1995) Semin Oncol 22:84–87). Movement of paclitaxel in interstitial space, in spite of its relatively low molecular weight (853 Dalton), is likely to behave as a protein because of its extensive binding to proteins in interstitial fluid (Baguley B C et al. (1995) Clin Exp Pharmacol Physiol 22:825–828).
A recent study indicates that drug delivery to a tissue during regional therapy depends on the ability of the drug to penetrate the solid tissue. The study indicates that paclitaxel distribution in multicellular spheroids is limited to the periphery, but the barriers to paclitaxel penetration are not known (Nicholson et al. (1997) Eur. J. Cancer 33:1291–1298). Accordingly, approaches to delivering therapeutic agents to tissues that allow for penetration of the drug into the tissue are still needed.